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The Skaggs Institute For Chemical Biology
Scientific Report 1999-2000


Director's Overview


Rebek/SRSK/Photo

Julius Rebek, Jr., Ph.D.

The Skaggs Institute for Chemical Biology is now in its fifth year. The Institute is a product of the munificence of Aline and Sam Skaggs and supports research at the interface of chemistry and biology. Its long-term goal is the improvement of human health through cures for diseases. Many principal investigators and several full-time researchers are supported through The Skaggs Institute for Research: 29 principal investigators and more than 200 researchers are also members of the Departments of Chemistry, Cell Biology, Molecular Biology, Neurobiology, and Molecular and Experimental Medicine at The Scripps Research Institute. Research efforts are concentrated in organic synthesis, antibody catalysis, protein structure, RNA chemistry, and molecular recognition. Through its publications, the Institute has established a worldwide reputation in these areas.

Highlights of the past year include the recruitment of Peter Schultz. Peter's breadth of interest and phenomenal energy further tilt the landscape of chemical biology to La Jolla. While he continues his work as a codiscoverer of catalytic antibodies, he also strives to expand the genetic code and generally applies the combinatorial approach to research in biological chemistry.

Elsewhere in the Institute, progress in the use of catalytic antibodies grows: the other codiscoverer of these molecules, Richard Lerner, and new member Subhash Sinha have used catalytic antibodies to generate key intermediates for the total synthesis of epothilones, promising chemotherapeutic agents. In addition, the applications of these 2 investigators in unmasking prodrugs in collaboration with Carlos Barbas and his group are a new departure in drug delivery. Dr. Barbas and his group are also involved in antibody catalysis of the formation of bonds between carbon atoms and in chemical catalysis by modified DNA enzymes.

Kim Janda and his team also use catalytic antibodies to form carbon-carbon bonds and have developed new sensors for molecules derived from chemical weapons. Nerve gas agents can now be detected by monoclonal antibodies. M.G. Finn also evolves antibodies with specifically engineered catalytic sites for metal complexes. Ehud Keinan and his group have succeeded in assembling an antibody with a metalloporphyrin catalytic site. Steve Mayfield's research centers on the production of antibodies in microalgae. Proteins produced in plant systems are safe and offer the advantages of large-scale production. Such plant systems lead to valuable human therapeutic agents and other proteins that were prohibitively expensive only a decade ago.

Highlights of the accomplishments in chemistry last year include the synthesis of the anticancer epothilones and eleutherobins by K.C. Nicolaou, chairman of the Chemistry Department. These molecules were made individually first and then as combinatorial libraries. Dale Boger and members of his laboratory probed the interaction of antitumor antibiotics with DNA. For this research, they used organic synthesis to produce structural modifications extending even to mirror-image isomers of the natural products. They also continue to use solution-phase combinatorial chemistry.

Synthesis of biologically active natural products is a common theme in Erik Sorensen's research and recently led to the synthesis of hispidospermidin. In collaboration with Ben Cravatt and his group, members of Dr. Sorensen's group developed new affinity agents that allow visualization of protease activity in normal and diseased tissues. Members of the Cravatt group also examine the molecular messages used to communicate between physiologic systems.

Chi-Huey Wong's research centers on the use of enzymes for chemical synthesis. This focus has led to combinatorial synthesis of molecules that bind to RNA, a rapidly emerging target for development of new antibiotics. The organic chemistry of proteins is the focus of research in Jeff Kelly's group, particularly the conversion of peptide bonds and side chains into heterocycle derivatives. Small-molecule inhibitors of processes involved in amyloid diseases are also studied in his laboratory. Combinatorial chemistry has captivated Barry Sharpless and his group. They apply uniquely efficient chemical processes coupled with robotics technology to create diverse libraries of compounds for screening in collaborations with other groups in the Scripps community.

Reza Ghadiri and the members of his group confront the frontier of chemical biology with their attempts to convert inanimate chemical reactions into animate chemistry. They start with physics and chemistry and intend to approach biology by generating autocatalytic chemical networks that consist of protein- rather than nucleic acid­based molecules. In my laboratory, we are using encapsulation complexes to explore how molecules fit together. These complexes involve a molecular "guest" that is completely surrounded by a larger "host," assembled through weak intermolecular forces. The dynamics of these assemblies, their asymmetric derivatives, and their applications as nanoscale reaction vessels were described in last year's report.

Ernest Beutler, chairman of the Department of Molecular and Experimental Medicine, and his group study the regulation of apoptosis, or programmed cell death, by various protein families. Members of his group also study the recognition of DNA sequences by oncoproteins.

Gerald Edelman, chairman of the Department of Neurobiology, continues to forge ahead on the regulation, function, and signaling mechanisms of molecules involved in cell adhesion. These mechanisms are central to neural development and nerve regeneration, as well as to proliferation and differentiation of stem cells.

Efforts in the Department of Molecular Biology, headed by Peter Wright, include his use of multidimensional nuclear magnetic resonance to determine the 3-dimensional structures of macromolecules in solution. These studies have revealed many new protein-protein and protein-nucleic acid interactions involved in leukemia and several involved in cell adhesion. In John Tainer's group, protein structure in the solid state has yielded the crystal structure of molecules involved in DNA repair. The structural changes that accompany genetic mutations of proteins in diseases such as amyotrophic lateral sclerosis are a focus of Elizabeth Getzoff's research. These proteins recognize and deal with reactive forms of oxygen such as superoxide. The snapshots of enzymes in various states obtained by using multiwavelength anomalous diffraction have allowed Dr. Getzoff to see how sulfur and nitrogen are processed in biological systems.

Crystallography also led to a high-resolution structure of the T-cell receptor by Ian Wilson's group. The structure reveals how the subtle positioning of the MHC-peptide complexes can be associated with autoimmune diseases such as diabetes. Dr. Wilson and his group also determined the structures of erythropoietin receptor with both agonist and antagonist peptides. Progress on the synthesis of proteins was made by Phil Dawson and his coworkers by using solid-phase peptide synthesis. Assembly with chemical ligation allows the replacement of side chains through synthesis and gives rapid access to probes for the determination of protein-folding pathways.

Progress in the area of RNA chemistry includes the efforts of Paul Schimmel and his group, who study the rules of the genetic code. The remarkable enzymes that recognize both RNA and amino acids, the synthetases, also have editing functions and are involved in the correction of errors in translation. The self-assembly of RNA and its ability to act as a catalyst are explored in Martha Fedor's group. Kinetic studies have indicated how cleavage of the ribozymes responds to changes in sequence and tertiary structure.

The dynamics and the nature of the folding intermediates in RNA folding have yielded to the studies of Jamie Williamson and his coworkers. Folding can be accelerated or slowed at will by the subtleties of experimental conditions and mutations. The cleavage of RNA by DNA enzymes is one of the recent accomplishments of Gerald Joyce and his group. They used test-tube evolution to develop these novel nucleic acid catalysts, which have activity in cancer cells and apoptosis.

The nature of nucleic acid structure and why Nature chose the particular sugars and bases it did are questions being answered in the research of Albert Eschenmoser. Through chemical synthesis, he and his colleagues showed that other structures containing tetroses instead of pentoses can engage in cooperative base pairing and even cross-pairing with natural RNA. They are also examining the assembly of polypeptide chains on RNA to find a process of protein synthesis that was an evolutionary precursor to ribosomes.

The reports that follow expand these sketches in some detail and point to the greatest benefit that is derived from working in the Skaggs Institute for Chemical Biology: the collaborations and synergy that interlace the research programs and the personalities. The continued support of the Skaggs Institute encourages the long-term look at questions in chemical biology.

 

 







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